A dramatic increase in the incidence of nosocomial infections caused by Candida species has been observed in recent years. The incidence of hematogenously disseminated candidal infections increased 11-fold from 1980 to 1989. This increasing incidence has continued through the 1990s and into the 2000s. Infections by Candida species are now the fourth most common cause of nosocomial septicemia, are equal to that of Escherichia coli, and surpass the incidence caused by Klebsiella species. Furthermore, Candida species are the most common cause of deep-seated fungal infections in patients who have extensive bums. Up to 11% of individuals undergoing bone marrow transplantation and 13% of those having an orthotopic liver transplant will develop an invasive candidal infection.
C. albicans infections are difficult to diagnose and the organism can survive in vivo without causing overtly detectable disease symptoms and can cause overt disease symptoms that vary in site and in severity. The infection can be localized and superficial or systemic and disseminated. C. albicans possesses numerous mechanisms to adapt to host sites, and differential gene expression under these mechanisms. Candida albicans can switch between two morphologies: the blastospore (budding yeast) and filamentous (hyphae and pseudohyphae) phases. Candida mutants that are defective in genes regulating filamentation are reported to have reduced virulence in animal models. This reduced virulence suggests that the ability to change from a blastospore to a filament is a key virulence factor of C. albicans. To date, no essential effectors of these filamentation pathways have been identified in C. albicans. See Caesar-TonThat, T. C. and J. E. Cutler, “A monoclonal antibody to Candida albicans enhances mouse neutrophil candidacidal activity,” Infect. Immun. 65:5354-5357, 1997.
The identification of effectors in the regulatory pathways of the organism that contribute to virulence offers the opportunity for therapeutic intervention with methods or compositions that are superior to existing antifungal agents. The identification of cell surface proteins that effect a regulatory pathway involved in virulence is particularly promising because characterization of the proteins enables immunotherapeutic techniques that are superior to existing antifungal agents when fighting a candidal infection. Also, both passive and active vaccination techniques offer unique prophylactic or therapeutic utilities depending on the clinical setting.
While potent antifungal agents exist that are microbicidal for Candida, the attributable mortality of candidemia is approximately 38%, even with treatment with potent anti-fungal agents such as amphotericin B. Also, existing agents such as amphotericin B tend to exhibit undesirable toxicity. Although additional antifungals may be developed that are less toxic than amphotericin B, it is unlikely that agents will be developed that are more potent. Therefore, either passive or active immunotherapy to treat or prevent disseminated candidiasis is a promising alternative to standard antifungal therapy.
The virulence of Candida albicans is regulated by several putative virulence factors, of which adherence to host constituents and the ability to transform from yeast-to-hyphae are among the most critical in determining pathogenicity. Adherent strains of C. albicans are more virulent than less-adhesive strains. Moreover, the more frequently isolated pathogenic species exhibit greater adhesive capacity. Investigations to understand C. albicans adhesion have involved characterization of the cell surface, since this is the initial point of contact between fungus and host. Moreover, filmentation pathways and their effect on molecules and pathways are implicated in virulence.